Pericytes are vascular mural cells embedded in the basement membrane of blood microvessels. They extend their processes along the walls of brain capillaries, pre-capillary arterioles, and post-capillary venules. Pericytes are situated centrally within the neurovascular unit between brain endothelial cells, astrocytes and neurons. This unique position allows them to process and respond to signals from their neighboring cells generating functional responses that are critical for different central nervous system (CNS). Pericyte injury and/or degeneration are found in multiple neurological disorders exhibiting neurovascular dysfunction and BBB breakdown. However, the exact role of pericyte dysfunction and loss in the pathogenesis of these disorders remains at present unclear.
Studies in pericyte-deficient mouse models have been carried out almost exclusively in transgenic animals with embryonically disrupted angiogenic signaling between endothelial-derived platelet-derived growth factor BB (PDGF-BB) and platelet-derived growth factor receptor β (PDGFRβ) in pericytes. Albeit extremely useful for understanding pericyte biology and providing important initial insights into their role in regulating neurovascular functions, models of PDGF-BB and PDGFRβ deficiency are not pericyte specific. They cannot isolate the potential contribution of other PDGFRβ-expressing CNS cell types, or the developmental impact of embryonic loss of PDGFRβ signaling on neurovascular and possibly neuronal phenotype that develops later in adult life and aging brain. For instance, in addition to pericytes, vascular smooth muscle cells (VSMCs) express also PDGFRβ, and some studies suggest that even cultured neurons and embryonic neurons express PDGFRβ, although not confirmed in the embryonic CNS or adult brain by others.
Described herein is an inducible pericyte-specific Cre line using a double-promoter strategy. The Inventors ablated adult mouse pericytes expressing Cre-dependent diphtheria toxin receptor after toxin administration. Pericyte ablation led to a rapid dysregulation of cerebral blood flow and blood-brain barrier breakdown. This was followed by behavioral deficits and neurodegenerative changes. These findings show that circulatory deficits leading to secondary neurodegeneration develop immediately after pericyte loss. These data indicate that pericyte degeneration as seen in neurological disorders with neurovascular dysfunction can contribute to neurodegeneration, suggesting new therapeutic strategies focusing on this particular cell type.